The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor (Meunier et al., Nature 377, 1995, p. 532–535) which belongs to the family of opioid receptors and is to be found in many regions of the brain and spinal cord (Mollereau et al., FEBS Letters, 341, 1994, p. 33–38, Darland et al., Trends in Neurosciences, 21, 1998, p. 215–221). The peptide is characterized by a high affinity, with a Kd value of approximately 56 pM (Ardati et al., Mol. Pharmacol. 51, p. 816–824), and by a high selectivity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors, and the amino acid sequence of the nociceptin peptide has a strong similarity with those of the known opioid peptides. The nociceptin-induced activation of the receptor leads to an inhibition of adenylate cyclase via coupling with Gi/o proteins (Meunier et al., Nature 377, 1995, p. 532–535). Functional similarities of the μ, κ and δ opioid receptors with the ORL1 receptor also exist at the cellular level with respect to activation of the potassium channel (Matthes et al., Mol. Pharmacol. 50, 1996, p. 447–450; Vaughan et al., Br. J. Pharmacol. 117, 1996, p. 1609–1611) and inhibition of the L-, N- and P/Q-type calcium channels (Conner et al., Br. J. Pharmacol. 118, 1996, p. 205–207; Knoflach et al., J. Neuroscience 16, 1996, p. 6657–6664).
After intercerebroventicular administration, the nociceptin peptide shows a pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, p. 792–794; Hara et al., Br. J. Pharmacol. 121, 1997, p. 401–408). These findings can be explained as an inhibition of stress-induced analgesia (Mogil et al., Neurosci. Letters 214, 1996, p 131–134; and Neuroscience 75, 1996, p. 333–337). It has also been possible to detect an anxiolytic activity of nociceptin in this connection (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854–14858).
On the other hand, it has also been possible to demonstrate an antinociceptive effect of nociceptin in various animal models, in particular after intrathecal administration. Nociceptin inhibits the activity of kainate- or glutamate-stimulated posterior route ganglia neurones (Shu et al., Neuropeptides, 32, 1998, 567–571) or glutamate-stimulated spinal cord neurones (Faber et al., Br. J. Pharmacol., 119, 1996, p. 189–190); it has an antinociceptive action in the tail flick test in the mouse (King et al., Neurosci. Lett., 223, 1997, 113–116), in the flexor-reflex model in the rat (Xu et al., NeuroReport, 7, 1996, 2092–2094) and in the formalin test on the rat (Yamamoto et al., Neuroscience, 81, 1997, p. 249–254). It has also been possible to demonstrate an antinociceptive action of nociceptin in models for neuropathic pain (Yamamoto and Nozaki-Taguchi, Anesthesiology, 87, 1997), which is particularly interesting in as much as the activity of nociceptin increases after axotomy of spinal nerves. This is in contrast to conventional opioids, the activity of which decreases under these conditions (Abdulla and Smith, J. Neurosci. 18, 1998, p. 9685–9694).
The ORL1 receptor is furthermore also involved in the regulation of further physiological and pathophysiological processes. These include, inter alia, learning and memory formation (Sandin et al., Eur. J. Neurosci., 9, 1997, p. 194–197; Manabe et al., Nature, 394, 1997, p. 577–581), hearing ability (Nishi et al., EMBO J., 16, 1997, p. 1858–1864), food intake (Pomonis et al., NeuroReport, 8, 1996, p. 369–371), regulation of blood pressure (Gumusel et al., Life Sci., 60, 1997, p. 141–145; Campion and Kadowitz, Biochem. Biophys. Res. Comm., 234, 1997, p. 309–312), epilepsy (Gutiérrez et al., Abstract 536.18, Society for Neuroscience, Vol 24, 28th Ann. Meeting, Los Angeles, Nov. 7th–12th, 1998) and diuresis (Kapista et al., Life Sciences, 60, 1997, PL 15–21). An article by Calo et al. (Br. J. Pharmacol., 129, 2000, 1261–1283) gives an overview of the indications or biological processes in which the ORL1 receptor plays or with high probability could play a role. Those mentioned are, inter alia: analgesia, stimulation and regulation of food intake, influence on μ-agonists, such as morphine, treatment of withdrawal symptoms, reduction in the addiction potential of morphines, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter secretion, especially of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing of the cardiovascular system, initiation of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention diseases, intestinal motility (diarrhea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics is furthermore discussed.
The possible uses of compounds which bind to the ORL1 receptor and activate or inhibit it are correspondingly diverse.